{"gene":"OSBPL2","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2015,"finding":"OSBPL2 protein is expressed in stereocilia of cochlear outer and inner hair cells in mice, and interacts with the DFNA1 protein DIAPH1","method":"Immunohistochemistry in mouse cochlea; protein interaction noted from literature context","journal":"Orphanet journal of rare diseases","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by immunohistochemistry with functional context; single lab","pmids":["25759012"],"is_preprint":false},{"year":2019,"finding":"OSBPL2 deletion increases cholesterol biosynthesis by reducing AMPK activity, leading to upregulation of SREBP2, HMGCR, and HMGCS1; OSBPL2 interacts with ATIC (a key AMPK activator), and loss of OSBPL2 increases total cholesterol and ROS with mitochondrial damage","method":"CRISPR/Cas9 KO in OC1 cells and zebrafish, RNA-seq, Co-IP (OSBPL2–ATIC interaction), biochemical assays for cholesterol and ROS","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — KO with defined phenotype plus Co-IP interaction; single lab with multiple methods","pmids":["31427568"],"is_preprint":false},{"year":2019,"finding":"OSBPL2 deficiency upregulates SQLE expression by suppressing AMPK signaling, which allows SP1 and SREBF2 to enter the nucleus and bind functional sites in the SQLE promoter, increasing intracellular cholesterol and cholesteryl ester","method":"CRISPR/Cas9 KO HeLa cells, RNA-seq, dual-luciferase reporter assay, RNA interference","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 1–2 — luciferase reporter plus KO transcriptomics, single lab","pmids":["31356817"],"is_preprint":false},{"year":2019,"finding":"OSBPL2 deficiency impairs focal adhesion morphology characterized by inhibited FAK activity and impaired cell adhesion in auditory OC-1 cells, with pathway analysis implicating lipid metabolism, cell adhesion, extracellular matrix, and ubiquitination","method":"CRISPR/Cas9 KO in OC-1 cells and zebrafish, RNA-seq, protein-protein interaction analysis, cell adhesion assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — KO with defined cellular phenotype (FAK activity, focal adhesion); single lab","pmids":["31629475"],"is_preprint":false},{"year":2018,"finding":"25-hydroxycholesterol downregulates OSBPL2 transcription via the p53/SREBF2/NFYA signaling pathway; NFYA and PLAG1 participate in basal transcription of OSBPL2 by binding its promoter","method":"Dual-luciferase reporter assay, transcriptome sequencing, RNA interference in HeLa cells","journal":"The Journal of steroid biochemistry and molecular biology","confidence":"Medium","confidence_rationale":"Tier 1–2 — luciferase reporter plus transcriptomics and RNAi; single lab","pmids":["30391516"],"is_preprint":false},{"year":2020,"finding":"OSBPL2 links the endoplasmic reticulum with lipid droplets, binds COPB1, and mediates ATGL transport from the ER to the lipid droplet surface, thereby regulating lipid droplet lipolysis","method":"Co-IP (OSBPL2–COPB1 interaction), subcellular fractionation/localization, KO cell lines, functional lipolysis assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP interaction plus functional transport assay; single lab","pmids":["32650117"],"is_preprint":false},{"year":2022,"finding":"Mutant OSBPL2 (frameshift) accumulates intracellularly, binds autophagy proteins, causes defective endolysosomal homeostasis and impaired autophagy; transgenic mice expressing mutant OSBPL2 exhibit hearing loss while KO mice do not, demonstrating toxic gain-of-function proteinopathy; rapamycin decreases mutant accumulation and partially rescues hearing loss","method":"Transgenic and KO mouse models, Co-IP (mutant OSBPL2–autophagy protein interaction), endolysosomal assays, rapamycin treatment in mice and human patients","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (transgenic/KO mice, Co-IP, cellular assays, human trial), replicated in vivo and in vitro","pmids":["35253614"],"is_preprint":false},{"year":2022,"finding":"OSBPL2 localizes to the base of kinocilia in hair cells and primary cilia in supporting cells; its deficiency increases PI(4,5)P2 on the cilia membrane, impairing ciliogenesis; this can be partially rescued by INPP5E overexpression; OSBPL2 deficiency also downregulates SMO and GLI3 in the Sonic Hedgehog signaling pathway","method":"KO mouse model, immunofluorescence localization, PI(4,5)P2 quantification, INPP5E rescue experiment, SHH pathway protein analysis in KO HEI-OC1 cells","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1–2 — direct localization with functional consequence, PI(4,5)P2 mechanistic rescue, KO mouse phenotype; multiple methods in single study","pmids":["35041619"],"is_preprint":false},{"year":2024,"finding":"OSBPL2 directly interacts with PLCB3 and inhibits its ubiquitylation, thereby stabilizing PLCB3; OSBPL2 variants lead to enhanced ubiquitination and degradation of PLCB3, causing epidermal hyperkeratosis with aberrant keratinocyte proliferation and delayed terminal differentiation","method":"Co-IP (OSBPL2–PLCB3 interaction), ubiquitylation assay, exome sequencing, cell proliferation and differentiation assays","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus ubiquitylation assay with functional cellular phenotype; single lab","pmids":["38701954"],"is_preprint":false},{"year":2024,"finding":"OSBPL2 deficiency activates ERK signaling through the VCAN/AREG/EREG axis and promotes cancer cell migration/invasion; OSBPL2 loss also facilitates metastasis via PARP1/ZEB1 pathway in colorectal cancer cells","method":"KO/knockdown in colorectal cancer cells, ERK pathway inhibitor (SCH772984) and PARP1 inhibitor (AG14361) rescue, migration/invasion assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — KO with defined pathway inhibitor rescue and cellular phenotype; single lab","pmids":["38267463"],"is_preprint":false},{"year":2025,"finding":"OSBPL2 deficiency inhibits Rho/ROCK2 signaling and downregulates phosphorylated ERM (p-ERM), resulting in abnormal F-actin morphology in HEI-OC1 cells and stereociliary defects in mouse hair cells","method":"KO mouse model and HEI-OC1 KO cells, Western blot for ROCK2/p-ERM, F-actin staining, scanning electron microscopy of stereocilia","journal":"Journal of biomedical research","confidence":"Medium","confidence_rationale":"Tier 2 — KO with defined pathway (Rho/ROCK2/p-ERM) and morphological phenotype; single lab","pmids":["40391522"],"is_preprint":false},{"year":2025,"finding":"OSBPL2 deficiency in stria vascularis impairs the cochlear blood-labyrinth barrier by disrupting tight junctions and inducing inflammation-mediated apoptosis via NF-κB signaling activation","method":"Osbpl2-KO mice with FITC-dextran permeability assay, OSBPL2-deficient HUVECs endothelial permeability assay, immunofluorescence of tight junctions, NF-κB pathway analysis","journal":"Hearing research","confidence":"Medium","confidence_rationale":"Tier 2 — KO in vivo and in vitro with functional permeability readout and pathway placement; single lab","pmids":["40975921"],"is_preprint":false},{"year":2024,"finding":"OSBPL2 knockdown in H2O2-treated HEI-OC1 cells sensitizes cells to apoptosis by inhibiting the AKT signaling pathway, which in turn inactivates FOXG1; AKT activation by SC79 partially rescues apoptosis in OSBPL2-knockdown cells, and this rescue is reversed by FOXG1 silencing","method":"siRNA knockdown, AKT inhibitor (MK2206) and activator (SC79), FOXG1 siRNA rescue experiment, apoptosis assays in HEI-OC1 cells","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 — epistatic rescue with chemical tools and siRNA; single lab, multiple interventions","pmids":["39475791"],"is_preprint":false},{"year":2026,"finding":"OSBPL2 binds HSP90β; OSBPL2 deficiency inhibits ACSL4 expression, alters hepatic fatty acid distribution by impairing lipolysis, and confers resistance to ferroptosis via the ACSL4-mediated ferroptosis pathway, attenuating diet-induced liver fibrosis","method":"Co-IP (OSBPL2–HSP90β), KO mouse model on high-fat diet, ACSL4 expression analysis, ferroptosis assays, liver fibrosis phenotyping","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus KO with defined ferroptosis pathway phenotype; single lab","pmids":["42006332"],"is_preprint":false}],"current_model":"OSBPL2 is a lipid transfer/oxysterol-binding protein that regulates intracellular cholesterol homeostasis (via AMPK/SREBP2/SQLE signaling), lipid droplet lipolysis (by linking the ER to lipid droplets through COPB1 and mediating ATGL transport), ciliogenesis (by controlling PI(4,5)P2 levels at the cilia membrane and Sonic Hedgehog signaling), and actin cytoskeletal organization (via Rho/ROCK2/p-ERM); frameshift mutations cause a toxic gain-of-function proteinopathy in which mutant protein accumulates, binds autophagy machinery, impairs endolysosomal homeostasis, and produces progressive hearing loss (DFNA67), while loss-of-function additionally disrupts the cochlear blood-labyrinth barrier through NF-κB activation, interacts with PLCB3 to regulate its stability, and binds HSP90β to modulate ferroptosis via ACSL4."},"narrative":{"teleology":[{"year":2015,"claim":"Establishing OSBPL2 as a cochlear protein: its localization to stereocilia of hair cells and interaction with the deafness protein DIAPH1 placed it in the auditory mechanotransduction apparatus for the first time.","evidence":"Immunohistochemistry in mouse cochlea with protein interaction context","pmids":["25759012"],"confidence":"Medium","gaps":["DIAPH1 interaction not validated by reciprocal Co-IP","Functional consequence of stereociliary localization untested","No hearing phenotype demonstrated"]},{"year":2018,"claim":"Understanding OSBPL2 transcriptional regulation: 25-hydroxycholesterol was shown to repress OSBPL2 transcription via p53/SREBF2/NFYA, revealing a feedback loop linking oxysterol sensing to OSBPL2 expression.","evidence":"Dual-luciferase reporter assay and RNAi in HeLa cells","pmids":["30391516"],"confidence":"Medium","gaps":["In vivo relevance of oxysterol-mediated feedback not tested","Whether other oxysterols similarly regulate OSBPL2 is unknown"]},{"year":2019,"claim":"Defining the cholesterol-regulatory mechanism: OSBPL2 loss was shown to decrease AMPK activity (via lost ATIC interaction), de-repress SREBP2 and its targets HMGCR/HMGCS1/SQLE, and elevate intracellular cholesterol and ROS, establishing OSBPL2 as a cholesterol homeostasis regulator acting through AMPK signaling.","evidence":"CRISPR KO in OC1 cells and zebrafish, Co-IP for OSBPL2–ATIC, RNA-seq, dual-luciferase reporter for SQLE promoter","pmids":["31427568","31356817"],"confidence":"Medium","gaps":["ATIC interaction validated by single Co-IP without domain mapping","Whether OSBPL2 lipid-binding activity is required for AMPK regulation is unknown","Cell adhesion and FAK impairment noted but mechanistic link to cholesterol not resolved"]},{"year":2020,"claim":"Revealing a lipid droplet tethering function: OSBPL2 was found to physically bridge the ER to lipid droplets through COPB1 interaction and to transport ATGL to lipid droplet surfaces, providing a direct mechanism for its role in lipolysis.","evidence":"Co-IP for OSBPL2–COPB1, subcellular fractionation, KO cell lipolysis assays","pmids":["32650117"],"confidence":"Medium","gaps":["Structural basis of ER–lipid droplet tethering undefined","Whether lipid transfer activity is required for ATGL transport not tested","COPB1 interaction not confirmed by independent lab"]},{"year":2022,"claim":"Establishing the disease mechanism for DFNA67: transgenic mice expressing frameshift mutant OSBPL2 developed hearing loss while KO mice did not, proving a toxic gain-of-function proteinopathy in which mutant protein sequesters autophagy machinery and impairs endolysosomal function; rapamycin partially rescued the phenotype.","evidence":"Transgenic and KO mouse models, Co-IP with autophagy proteins, endolysosomal assays, rapamycin treatment in mice and patients","pmids":["35253614"],"confidence":"High","gaps":["Identity of sequestered autophagy proteins not fully characterized","Long-term efficacy of rapamycin in patients unknown","Whether all OSBPL2 frameshift mutations produce the same toxic protein unclear"]},{"year":2022,"claim":"Uncovering a ciliogenesis role: OSBPL2 localizes to cilia bases and its loss elevates ciliary PI(4,5)P2, impairing ciliogenesis and Sonic Hedgehog signaling (SMO, GLI3); INPP5E overexpression partially rescued the PI(4,5)P2 defect, linking OSBPL2's phosphoinositide regulation to cilium formation.","evidence":"KO mouse and HEI-OC1 cells, immunofluorescence, PI(4,5)P2 quantification, INPP5E rescue","pmids":["35041619"],"confidence":"High","gaps":["Whether OSBPL2 directly transfers PI(4,5)P2 or acts indirectly is unresolved","Contribution of ciliogenesis defects versus stereocilia defects to hearing loss not separated"]},{"year":2024,"claim":"Expanding functional scope: OSBPL2 was shown to stabilize PLCB3 by inhibiting its ubiquitylation, with OSBPL2 variants causing keratinocyte hyperkeratosis, and separately OSBPL2 loss was found to promote colorectal cancer migration via ERK/PARP1/ZEB1 and to sensitize hair cells to apoptosis via AKT/FOXG1 inactivation.","evidence":"Co-IP and ubiquitylation assays for PLCB3; KO colorectal cancer cells with ERK/PARP1 inhibitor rescue; siRNA knockdown with AKT activator/inhibitor rescue in HEI-OC1","pmids":["38701954","38267463","39475791"],"confidence":"Medium","gaps":["PLCB3 stabilization mechanism (which E3 ligase is antagonized) unknown","Relevance of colorectal cancer findings to physiological OSBPL2 function unclear","AKT/FOXG1 pathway link specific to oxidative stress context"]},{"year":2025,"claim":"Defining the actin-regulatory and barrier-integrity functions: OSBPL2 deficiency was shown to impair stereocilia through Rho/ROCK2/p-ERM downregulation and to disrupt the cochlear blood-labyrinth barrier via NF-κB–driven tight junction loss and inflammation-mediated apoptosis.","evidence":"KO mouse and HEI-OC1 cells with ROCK2/p-ERM Western blot, SEM of stereocilia; KO mice with FITC-dextran permeability, HUVEC permeability assay, NF-κB analysis","pmids":["40391522","40975921"],"confidence":"Medium","gaps":["How OSBPL2 activates RhoA upstream of ROCK2 is undefined","Whether NF-κB activation is a direct or secondary consequence of OSBPL2 loss unclear","Single-lab findings for both phenotypes"]},{"year":2025,"claim":"Linking OSBPL2 to ferroptosis: OSBPL2 binds HSP90β and its deficiency suppresses ACSL4, altering hepatic fatty acid composition and conferring ferroptosis resistance that attenuates diet-induced liver fibrosis.","evidence":"Co-IP for OSBPL2–HSP90β, KO mouse on high-fat diet, ferroptosis assays, liver fibrosis phenotyping","pmids":["42006332"],"confidence":"Medium","gaps":["HSP90β interaction not confirmed by independent lab","Mechanism connecting HSP90β binding to ACSL4 expression unresolved","Physiological relevance of ferroptosis resistance in normal hepatocytes unclear"]},{"year":null,"claim":"Major open question: whether OSBPL2's lipid transfer activity is directly required for its diverse signaling roles (AMPK, ciliogenesis, actin regulation), and how a single protein coordinates cholesterol, phosphoinositide, and fatty acid pathways across different tissues remains mechanistically unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No crystal structure or lipid-binding mutant analysis separating transfer activity from scaffolding","Tissue-specific interactomes not systematically mapped","Relative contribution of loss-of-function versus toxic gain-of-function to DFNA67 pathology in human patients not fully delineated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,2,5,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,6]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[5]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[5]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[7]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,10]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,2,5,13]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,9,10,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,9]}],"complexes":[],"partners":["ATIC","COPB1","PLCB3","HSP90AB1","DIAPH1"],"other_free_text":[]},"mechanistic_narrative":"OSBPL2 is a lipid transfer protein that integrates cholesterol homeostasis, phosphoinositide regulation, and cytoskeletal organization across multiple cell types. It maintains intracellular cholesterol levels by sustaining AMPK activity through interaction with ATIC, thereby suppressing SREBP2-driven cholesterol biosynthesis genes including SQLE and HMGCR [PMID:31427568, PMID:31356817]; it also bridges the endoplasmic reticulum to lipid droplets via COPB1 binding to mediate ATGL transport and lipid droplet lipolysis [PMID:32650117]. In cochlear hair cells, OSBPL2 controls cilia membrane PI(4,5)P2 levels and Sonic Hedgehog signaling to support ciliogenesis, and maintains stereocilia architecture through Rho/ROCK2/phospho-ERM–dependent actin organization [PMID:35041619, PMID:40391522]. Frameshift mutations in OSBPL2 cause autosomal dominant hearing loss (DFNA67) through a toxic gain-of-function proteinopathy in which mutant protein accumulates, sequesters autophagy machinery, and disrupts endolysosomal homeostasis—a phenotype partially rescued by rapamycin [PMID:35253614]."},"prefetch_data":{"uniprot":{"accession":"Q9H1P3","full_name":"Oxysterol-binding protein-related protein 2","aliases":[],"length_aa":480,"mass_kda":55.2,"function":"Intracellular transport protein that binds sterols and phospholipids and mediates lipid transport between intracellular compartments. Increases plasma membrane cholesterol levels and decreases phosphatidylinositol-4,5-bisphosphate levels in the cell membrane (PubMed:30581148). Binds phosphoinositides, such as phosphatidylinositol-4,5-bisphosphate (PubMed:30581148). Exhibits strong binding to phosphatidic acid and weak binding to phosphatidylinositol 3-phosphate (PubMed:11279184). Binds cholesterol, dehydroergosterol, 22(R)-hydroxycholesterol and 25-hydroxycholesterol (in vitro) (PubMed:17428193, PubMed:19224871, PubMed:30581148)","subcellular_location":"Cytoplasm, cytosol; Lipid droplet; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9H1P3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OSBPL2","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OSBPL2","total_profiled":1310},"omim":[{"mim_id":"621400","title":"DYSCHROMATOSIS, ICHTHYOSIS, DEAFNESS, AND ATOPIC DISEASE; DIDA","url":"https://www.omim.org/entry/621400"},{"mim_id":"616340","title":"DEAFNESS, AUTOSOMAL DOMINANT 67; DFNA67","url":"https://www.omim.org/entry/616340"},{"mim_id":"606731","title":"OXYSTEROL-BINDING PROTEIN-LIKE PROTEIN 2; OSBPL2","url":"https://www.omim.org/entry/606731"},{"mim_id":"606730","title":"OXYSTEROL-BINDING PROTEIN-LIKE PROTEIN 1A; OSBPL1A","url":"https://www.omim.org/entry/606730"},{"mim_id":"600230","title":"PHOSPHOLIPASE C, BETA-3; PLCB3","url":"https://www.omim.org/entry/600230"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/OSBPL2"},"hgnc":{"alias_symbol":["KIAA0772","ORP-2","DFNA67"],"prev_symbol":[]},"alphafold":{"accession":"Q9H1P3","domains":[{"cath_id":"2.40.160.120","chopping":"77-325_355-405_444-471","consensus_level":"medium","plddt":93.9618,"start":77,"end":471}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H1P3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H1P3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H1P3-F1-predicted_aligned_error_v6.png","plddt_mean":83.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OSBPL2","jax_strain_url":"https://www.jax.org/strain/search?query=OSBPL2"},"sequence":{"accession":"Q9H1P3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H1P3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H1P3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H1P3"}},"corpus_meta":[{"pmid":"25077649","id":"PMC_25077649","title":"Identification of OSBPL2 as a novel candidate gene for progressive nonsyndromic hearing loss by whole-exome sequencing.","date":"2014","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25077649","citation_count":50,"is_preprint":false},{"pmid":"25759012","id":"PMC_25759012","title":"OSBPL2 encodes a protein of inner and outer hair cell stereocilia and is mutated in autosomal dominant hearing loss (DFNA67).","date":"2015","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/25759012","citation_count":44,"is_preprint":false},{"pmid":"31427568","id":"PMC_31427568","title":"Deletion of OSBPL2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting AMPK activity.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31427568","citation_count":33,"is_preprint":false},{"pmid":"35253614","id":"PMC_35253614","title":"OSBPL2 mutations impair autophagy and lead to hearing loss, potentially remedied by rapamycin.","date":"2022","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/35253614","citation_count":30,"is_preprint":false},{"pmid":"32650117","id":"PMC_32650117","title":"OSBPL2 Is Required for the Binding of COPB1 to ATGL and the Regulation of Lipid Droplet Lipolysis.","date":"2020","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/32650117","citation_count":28,"is_preprint":false},{"pmid":"31356817","id":"PMC_31356817","title":"OSBPL2 deficiency upregulate SQLE expression increasing intracellular cholesterol and cholesteryl ester by AMPK/SP1 and SREBF2 signalling pathway.","date":"2019","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/31356817","citation_count":28,"is_preprint":false},{"pmid":"31451425","id":"PMC_31451425","title":"OSBPL2-disrupted pigs recapitulate dual features of human hearing loss and hypercholesterolaemia.","date":"2019","source":"Journal of genetics and genomics = Yi chuan xue bao","url":"https://pubmed.ncbi.nlm.nih.gov/31451425","citation_count":23,"is_preprint":false},{"pmid":"33854310","id":"PMC_33854310","title":"Circ-OSBPL2 Contributes to Smoke-Related Chronic Obstructive Pulmonary Disease by Targeting miR-193a-5p/BRD4 Axis.","date":"2021","source":"International journal of chronic obstructive pulmonary disease","url":"https://pubmed.ncbi.nlm.nih.gov/33854310","citation_count":19,"is_preprint":false},{"pmid":"38267463","id":"PMC_38267463","title":"Collagen I-induced VCAN/ERK signaling and PARP1/ZEB1-mediated metastasis facilitate OSBPL2 defect to promote colorectal cancer progression.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38267463","citation_count":18,"is_preprint":false},{"pmid":"35305988","id":"PMC_35305988","title":"circRNA Acbd6 promotes neural stem cell differentiation into cholinergic neurons via the miR-320-5p-Osbpl2 axis.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35305988","citation_count":17,"is_preprint":false},{"pmid":"35041619","id":"PMC_35041619","title":"Mutations in OSBPL2 cause hearing loss associated with primary cilia defects via sonic hedgehog signaling.","date":"2022","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/35041619","citation_count":14,"is_preprint":false},{"pmid":"30894143","id":"PMC_30894143","title":"A novel pathogenic variant in OSBPL2 linked to hereditary late-onset deafness in a Mongolian family.","date":"2019","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30894143","citation_count":11,"is_preprint":false},{"pmid":"31629475","id":"PMC_31629475","title":"Comparative transcriptome analysis of auditory OC-1 cells and zebrafish inner ear tissues in the absence of human OSBPL2 orthologues.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31629475","citation_count":6,"is_preprint":false},{"pmid":"30391516","id":"PMC_30391516","title":"25-hydroxycholesterol down-regulates oxysterol binding protein like 2 (OSBPL2) via the p53/SREBF2/NFYA signaling pathway.","date":"2018","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/30391516","citation_count":6,"is_preprint":false},{"pmid":"40975921","id":"PMC_40975921","title":"OSBPL2 deficiency impaired cochlear blood-labyrinth barrier via activation of NF-κB signaling pathway.","date":"2025","source":"Hearing research","url":"https://pubmed.ncbi.nlm.nih.gov/40975921","citation_count":2,"is_preprint":false},{"pmid":"39475791","id":"PMC_39475791","title":"OSBPL2 inhibition leads to apoptosis of cochlea hair cells in age-related hearing loss by inhibiting the AKT/FOXG1 signaling pathway.","date":"2024","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/39475791","citation_count":2,"is_preprint":false},{"pmid":"40391522","id":"PMC_40391522","title":"OSBPL2 deficiency inhibits Rho/ROCK2/p-ERM signaling and impairs actin cytoskeletal regulation in auditory cells.","date":"2025","source":"Journal of biomedical research","url":"https://pubmed.ncbi.nlm.nih.gov/40391522","citation_count":1,"is_preprint":false},{"pmid":"38701954","id":"PMC_38701954","title":"OSBPL2 compound heterozygous variants cause dyschromatosis, ichthyosis, deafness and atopic disease syndrome.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/38701954","citation_count":0,"is_preprint":false},{"pmid":"41017354","id":"PMC_41017354","title":"[OSBPL2-related autosomal dominant hearing loss: a family analysis and literature review].","date":"2025","source":"Zhonghua yi xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/41017354","citation_count":0,"is_preprint":false},{"pmid":"41645290","id":"PMC_41645290","title":"OSBPL2-mediated lipid metabolism alteration governs lung cancer stem cells properties.","date":"2026","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/41645290","citation_count":0,"is_preprint":false},{"pmid":"42006332","id":"PMC_42006332","title":"OSBPL2 deficiency alleviates diet-induced MASLD by reducing ACSL4-mediated ferroptosis.","date":"2026","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/42006332","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.28.25323104","title":"Intragenic deletions from whole genome sequencing of 1054 suicide deaths","date":"2025-03-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.28.25323104","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12545,"output_tokens":3338,"usd":0.043853},"stage2":{"model":"claude-opus-4-6","input_tokens":6763,"output_tokens":3045,"usd":0.16491},"total_usd":0.208763,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"OSBPL2 protein is expressed in stereocilia of cochlear outer and inner hair cells in mice, and interacts with the DFNA1 protein DIAPH1\",\n      \"method\": \"Immunohistochemistry in mouse cochlea; protein interaction noted from literature context\",\n      \"journal\": \"Orphanet journal of rare diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by immunohistochemistry with functional context; single lab\",\n      \"pmids\": [\"25759012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OSBPL2 deletion increases cholesterol biosynthesis by reducing AMPK activity, leading to upregulation of SREBP2, HMGCR, and HMGCS1; OSBPL2 interacts with ATIC (a key AMPK activator), and loss of OSBPL2 increases total cholesterol and ROS with mitochondrial damage\",\n      \"method\": \"CRISPR/Cas9 KO in OC1 cells and zebrafish, RNA-seq, Co-IP (OSBPL2–ATIC interaction), biochemical assays for cholesterol and ROS\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined phenotype plus Co-IP interaction; single lab with multiple methods\",\n      \"pmids\": [\"31427568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OSBPL2 deficiency upregulates SQLE expression by suppressing AMPK signaling, which allows SP1 and SREBF2 to enter the nucleus and bind functional sites in the SQLE promoter, increasing intracellular cholesterol and cholesteryl ester\",\n      \"method\": \"CRISPR/Cas9 KO HeLa cells, RNA-seq, dual-luciferase reporter assay, RNA interference\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — luciferase reporter plus KO transcriptomics, single lab\",\n      \"pmids\": [\"31356817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OSBPL2 deficiency impairs focal adhesion morphology characterized by inhibited FAK activity and impaired cell adhesion in auditory OC-1 cells, with pathway analysis implicating lipid metabolism, cell adhesion, extracellular matrix, and ubiquitination\",\n      \"method\": \"CRISPR/Cas9 KO in OC-1 cells and zebrafish, RNA-seq, protein-protein interaction analysis, cell adhesion assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined cellular phenotype (FAK activity, focal adhesion); single lab\",\n      \"pmids\": [\"31629475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"25-hydroxycholesterol downregulates OSBPL2 transcription via the p53/SREBF2/NFYA signaling pathway; NFYA and PLAG1 participate in basal transcription of OSBPL2 by binding its promoter\",\n      \"method\": \"Dual-luciferase reporter assay, transcriptome sequencing, RNA interference in HeLa cells\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — luciferase reporter plus transcriptomics and RNAi; single lab\",\n      \"pmids\": [\"30391516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OSBPL2 links the endoplasmic reticulum with lipid droplets, binds COPB1, and mediates ATGL transport from the ER to the lipid droplet surface, thereby regulating lipid droplet lipolysis\",\n      \"method\": \"Co-IP (OSBPL2–COPB1 interaction), subcellular fractionation/localization, KO cell lines, functional lipolysis assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP interaction plus functional transport assay; single lab\",\n      \"pmids\": [\"32650117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mutant OSBPL2 (frameshift) accumulates intracellularly, binds autophagy proteins, causes defective endolysosomal homeostasis and impaired autophagy; transgenic mice expressing mutant OSBPL2 exhibit hearing loss while KO mice do not, demonstrating toxic gain-of-function proteinopathy; rapamycin decreases mutant accumulation and partially rescues hearing loss\",\n      \"method\": \"Transgenic and KO mouse models, Co-IP (mutant OSBPL2–autophagy protein interaction), endolysosomal assays, rapamycin treatment in mice and human patients\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (transgenic/KO mice, Co-IP, cellular assays, human trial), replicated in vivo and in vitro\",\n      \"pmids\": [\"35253614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OSBPL2 localizes to the base of kinocilia in hair cells and primary cilia in supporting cells; its deficiency increases PI(4,5)P2 on the cilia membrane, impairing ciliogenesis; this can be partially rescued by INPP5E overexpression; OSBPL2 deficiency also downregulates SMO and GLI3 in the Sonic Hedgehog signaling pathway\",\n      \"method\": \"KO mouse model, immunofluorescence localization, PI(4,5)P2 quantification, INPP5E rescue experiment, SHH pathway protein analysis in KO HEI-OC1 cells\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct localization with functional consequence, PI(4,5)P2 mechanistic rescue, KO mouse phenotype; multiple methods in single study\",\n      \"pmids\": [\"35041619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OSBPL2 directly interacts with PLCB3 and inhibits its ubiquitylation, thereby stabilizing PLCB3; OSBPL2 variants lead to enhanced ubiquitination and degradation of PLCB3, causing epidermal hyperkeratosis with aberrant keratinocyte proliferation and delayed terminal differentiation\",\n      \"method\": \"Co-IP (OSBPL2–PLCB3 interaction), ubiquitylation assay, exome sequencing, cell proliferation and differentiation assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus ubiquitylation assay with functional cellular phenotype; single lab\",\n      \"pmids\": [\"38701954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OSBPL2 deficiency activates ERK signaling through the VCAN/AREG/EREG axis and promotes cancer cell migration/invasion; OSBPL2 loss also facilitates metastasis via PARP1/ZEB1 pathway in colorectal cancer cells\",\n      \"method\": \"KO/knockdown in colorectal cancer cells, ERK pathway inhibitor (SCH772984) and PARP1 inhibitor (AG14361) rescue, migration/invasion assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined pathway inhibitor rescue and cellular phenotype; single lab\",\n      \"pmids\": [\"38267463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OSBPL2 deficiency inhibits Rho/ROCK2 signaling and downregulates phosphorylated ERM (p-ERM), resulting in abnormal F-actin morphology in HEI-OC1 cells and stereociliary defects in mouse hair cells\",\n      \"method\": \"KO mouse model and HEI-OC1 KO cells, Western blot for ROCK2/p-ERM, F-actin staining, scanning electron microscopy of stereocilia\",\n      \"journal\": \"Journal of biomedical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined pathway (Rho/ROCK2/p-ERM) and morphological phenotype; single lab\",\n      \"pmids\": [\"40391522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OSBPL2 deficiency in stria vascularis impairs the cochlear blood-labyrinth barrier by disrupting tight junctions and inducing inflammation-mediated apoptosis via NF-κB signaling activation\",\n      \"method\": \"Osbpl2-KO mice with FITC-dextran permeability assay, OSBPL2-deficient HUVECs endothelial permeability assay, immunofluorescence of tight junctions, NF-κB pathway analysis\",\n      \"journal\": \"Hearing research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO in vivo and in vitro with functional permeability readout and pathway placement; single lab\",\n      \"pmids\": [\"40975921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OSBPL2 knockdown in H2O2-treated HEI-OC1 cells sensitizes cells to apoptosis by inhibiting the AKT signaling pathway, which in turn inactivates FOXG1; AKT activation by SC79 partially rescues apoptosis in OSBPL2-knockdown cells, and this rescue is reversed by FOXG1 silencing\",\n      \"method\": \"siRNA knockdown, AKT inhibitor (MK2206) and activator (SC79), FOXG1 siRNA rescue experiment, apoptosis assays in HEI-OC1 cells\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistatic rescue with chemical tools and siRNA; single lab, multiple interventions\",\n      \"pmids\": [\"39475791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"OSBPL2 binds HSP90β; OSBPL2 deficiency inhibits ACSL4 expression, alters hepatic fatty acid distribution by impairing lipolysis, and confers resistance to ferroptosis via the ACSL4-mediated ferroptosis pathway, attenuating diet-induced liver fibrosis\",\n      \"method\": \"Co-IP (OSBPL2–HSP90β), KO mouse model on high-fat diet, ACSL4 expression analysis, ferroptosis assays, liver fibrosis phenotyping\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus KO with defined ferroptosis pathway phenotype; single lab\",\n      \"pmids\": [\"42006332\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OSBPL2 is a lipid transfer/oxysterol-binding protein that regulates intracellular cholesterol homeostasis (via AMPK/SREBP2/SQLE signaling), lipid droplet lipolysis (by linking the ER to lipid droplets through COPB1 and mediating ATGL transport), ciliogenesis (by controlling PI(4,5)P2 levels at the cilia membrane and Sonic Hedgehog signaling), and actin cytoskeletal organization (via Rho/ROCK2/p-ERM); frameshift mutations cause a toxic gain-of-function proteinopathy in which mutant protein accumulates, binds autophagy machinery, impairs endolysosomal homeostasis, and produces progressive hearing loss (DFNA67), while loss-of-function additionally disrupts the cochlear blood-labyrinth barrier through NF-κB activation, interacts with PLCB3 to regulate its stability, and binds HSP90β to modulate ferroptosis via ACSL4.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"OSBPL2 is a lipid transfer protein that integrates cholesterol homeostasis, phosphoinositide regulation, and cytoskeletal organization across multiple cell types. It maintains intracellular cholesterol levels by sustaining AMPK activity through interaction with ATIC, thereby suppressing SREBP2-driven cholesterol biosynthesis genes including SQLE and HMGCR [PMID:31427568, PMID:31356817]; it also bridges the endoplasmic reticulum to lipid droplets via COPB1 binding to mediate ATGL transport and lipid droplet lipolysis [PMID:32650117]. In cochlear hair cells, OSBPL2 controls cilia membrane PI(4,5)P2 levels and Sonic Hedgehog signaling to support ciliogenesis, and maintains stereocilia architecture through Rho/ROCK2/phospho-ERM–dependent actin organization [PMID:35041619, PMID:40391522]. Frameshift mutations in OSBPL2 cause autosomal dominant hearing loss (DFNA67) through a toxic gain-of-function proteinopathy in which mutant protein accumulates, sequesters autophagy machinery, and disrupts endolysosomal homeostasis—a phenotype partially rescued by rapamycin [PMID:35253614].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing OSBPL2 as a cochlear protein: its localization to stereocilia of hair cells and interaction with the deafness protein DIAPH1 placed it in the auditory mechanotransduction apparatus for the first time.\",\n      \"evidence\": \"Immunohistochemistry in mouse cochlea with protein interaction context\",\n      \"pmids\": [\"25759012\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"DIAPH1 interaction not validated by reciprocal Co-IP\",\n        \"Functional consequence of stereociliary localization untested\",\n        \"No hearing phenotype demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Understanding OSBPL2 transcriptional regulation: 25-hydroxycholesterol was shown to repress OSBPL2 transcription via p53/SREBF2/NFYA, revealing a feedback loop linking oxysterol sensing to OSBPL2 expression.\",\n      \"evidence\": \"Dual-luciferase reporter assay and RNAi in HeLa cells\",\n      \"pmids\": [\"30391516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo relevance of oxysterol-mediated feedback not tested\",\n        \"Whether other oxysterols similarly regulate OSBPL2 is unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defining the cholesterol-regulatory mechanism: OSBPL2 loss was shown to decrease AMPK activity (via lost ATIC interaction), de-repress SREBP2 and its targets HMGCR/HMGCS1/SQLE, and elevate intracellular cholesterol and ROS, establishing OSBPL2 as a cholesterol homeostasis regulator acting through AMPK signaling.\",\n      \"evidence\": \"CRISPR KO in OC1 cells and zebrafish, Co-IP for OSBPL2–ATIC, RNA-seq, dual-luciferase reporter for SQLE promoter\",\n      \"pmids\": [\"31427568\", \"31356817\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"ATIC interaction validated by single Co-IP without domain mapping\",\n        \"Whether OSBPL2 lipid-binding activity is required for AMPK regulation is unknown\",\n        \"Cell adhesion and FAK impairment noted but mechanistic link to cholesterol not resolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealing a lipid droplet tethering function: OSBPL2 was found to physically bridge the ER to lipid droplets through COPB1 interaction and to transport ATGL to lipid droplet surfaces, providing a direct mechanism for its role in lipolysis.\",\n      \"evidence\": \"Co-IP for OSBPL2–COPB1, subcellular fractionation, KO cell lipolysis assays\",\n      \"pmids\": [\"32650117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of ER–lipid droplet tethering undefined\",\n        \"Whether lipid transfer activity is required for ATGL transport not tested\",\n        \"COPB1 interaction not confirmed by independent lab\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Establishing the disease mechanism for DFNA67: transgenic mice expressing frameshift mutant OSBPL2 developed hearing loss while KO mice did not, proving a toxic gain-of-function proteinopathy in which mutant protein sequesters autophagy machinery and impairs endolysosomal function; rapamycin partially rescued the phenotype.\",\n      \"evidence\": \"Transgenic and KO mouse models, Co-IP with autophagy proteins, endolysosomal assays, rapamycin treatment in mice and patients\",\n      \"pmids\": [\"35253614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of sequestered autophagy proteins not fully characterized\",\n        \"Long-term efficacy of rapamycin in patients unknown\",\n        \"Whether all OSBPL2 frameshift mutations produce the same toxic protein unclear\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncovering a ciliogenesis role: OSBPL2 localizes to cilia bases and its loss elevates ciliary PI(4,5)P2, impairing ciliogenesis and Sonic Hedgehog signaling (SMO, GLI3); INPP5E overexpression partially rescued the PI(4,5)P2 defect, linking OSBPL2's phosphoinositide regulation to cilium formation.\",\n      \"evidence\": \"KO mouse and HEI-OC1 cells, immunofluorescence, PI(4,5)P2 quantification, INPP5E rescue\",\n      \"pmids\": [\"35041619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether OSBPL2 directly transfers PI(4,5)P2 or acts indirectly is unresolved\",\n        \"Contribution of ciliogenesis defects versus stereocilia defects to hearing loss not separated\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanding functional scope: OSBPL2 was shown to stabilize PLCB3 by inhibiting its ubiquitylation, with OSBPL2 variants causing keratinocyte hyperkeratosis, and separately OSBPL2 loss was found to promote colorectal cancer migration via ERK/PARP1/ZEB1 and to sensitize hair cells to apoptosis via AKT/FOXG1 inactivation.\",\n      \"evidence\": \"Co-IP and ubiquitylation assays for PLCB3; KO colorectal cancer cells with ERK/PARP1 inhibitor rescue; siRNA knockdown with AKT activator/inhibitor rescue in HEI-OC1\",\n      \"pmids\": [\"38701954\", \"38267463\", \"39475791\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"PLCB3 stabilization mechanism (which E3 ligase is antagonized) unknown\",\n        \"Relevance of colorectal cancer findings to physiological OSBPL2 function unclear\",\n        \"AKT/FOXG1 pathway link specific to oxidative stress context\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defining the actin-regulatory and barrier-integrity functions: OSBPL2 deficiency was shown to impair stereocilia through Rho/ROCK2/p-ERM downregulation and to disrupt the cochlear blood-labyrinth barrier via NF-κB–driven tight junction loss and inflammation-mediated apoptosis.\",\n      \"evidence\": \"KO mouse and HEI-OC1 cells with ROCK2/p-ERM Western blot, SEM of stereocilia; KO mice with FITC-dextran permeability, HUVEC permeability assay, NF-κB analysis\",\n      \"pmids\": [\"40391522\", \"40975921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How OSBPL2 activates RhoA upstream of ROCK2 is undefined\",\n        \"Whether NF-κB activation is a direct or secondary consequence of OSBPL2 loss unclear\",\n        \"Single-lab findings for both phenotypes\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linking OSBPL2 to ferroptosis: OSBPL2 binds HSP90β and its deficiency suppresses ACSL4, altering hepatic fatty acid composition and conferring ferroptosis resistance that attenuates diet-induced liver fibrosis.\",\n      \"evidence\": \"Co-IP for OSBPL2–HSP90β, KO mouse on high-fat diet, ferroptosis assays, liver fibrosis phenotyping\",\n      \"pmids\": [\"42006332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"HSP90β interaction not confirmed by independent lab\",\n        \"Mechanism connecting HSP90β binding to ACSL4 expression unresolved\",\n        \"Physiological relevance of ferroptosis resistance in normal hepatocytes unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open question: whether OSBPL2's lipid transfer activity is directly required for its diverse signaling roles (AMPK, ciliogenesis, actin regulation), and how a single protein coordinates cholesterol, phosphoinositide, and fatty acid pathways across different tissues remains mechanistically unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No crystal structure or lipid-binding mutant analysis separating transfer activity from scaffolding\",\n        \"Tissue-specific interactomes not systematically mapped\",\n        \"Relative contribution of loss-of-function versus toxic gain-of-function to DFNA67 pathology in human patients not fully delineated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 2, 5, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 2, 5, 13]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 9, 10, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ATIC\",\n      \"COPB1\",\n      \"PLCB3\",\n      \"HSP90AB1\",\n      \"DIAPH1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}